While several cellular mechanisms that underlie learning and memory have been well-studied, little is known about the genetic components that contribute to proper memory formation, retention, and retrieval. A special class of genes called immediate early genes (IEGs) is rapidly expressed in neurons in response to activity, and has been implicated in learning and memory. We have initiated a genome-wide analysis of Drosophila melanogaster brains in order to discover novel IEGs that may underlie memory. Our preliminary results have revealed 278 candidate IEGs that are expressed differently in the Drosophila brain after exposure to sensory stimulation, and we have used a high-throughput behavior screen to implicate 28 of these genes so far in learning and memory. In addition to the classical IEGs that are rapidly up-regulated in response to neuronal activity, we have also identified 87 genes that are down-regulated immediately following stimulation, several of which we have implicated in memory using our behavior screen. The goal of this proposal is to delineate the molecular mechanisms by which 6 novel IEGs that we identified, that are conserved in humans, are necessary for learning and memory. We have selected 3 up-regulated genes (CG11964, sallimus, and Amylase distal) and 3 down-regulated genes (Heat-shock-protein-70Ab, Heat-shock-protein- 70Ba, and maggie) that have a variety of molecular functions, which should provide an understanding of the diverse molecular and cellular mechanisms necessary for memory formation and retrieval. We will validate that our IEGs are critical for learning using standard Drosophila tools and techniques such as alternative allele lines and deficiency stocks, and we will map expression of the genes in the brain using RNA probes and antibodies to delineate specific regions that are needed for several different types of learning. We will also investigate a potential developmental role for the genes by knocking down gene expression with RNAi following development. The outcome of our studies will specify the methods by which these 6 specific novel genes are critical for proper memory function. Our results will also provide a greater understanding of normal learning and memory mechanisms, as well as potential therapeutic targets for neurological diseases that result in memory loss.